Abstract 1108: A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters

Abstract

Abstract Cancer is the second leading cause of death in the US. Multidrug resistance (MDR) and the resulting ineffectiveness of the drug treatment are responsible for most relapses of cancer and cancer-related death. One major mechanism of MDR is the efflux of multiple drugs mediated by ATP-binding Cassette (ABC) multidrug transporters. ABC transporters pump drugs with different structures and mechanisms of action out of cancer cells using ATP-provided energy. The opportunistic uptake of extracellular molecules has been named as a key emerging hallmark of cancer metabolism1. Intratumoral extracellular ATP levels of various cancer types are 103 to 104 times higher than those in their corresponding normal tissues2. Our previous studies have shown that extracellular ATP is internalized by cancer cell via macropinocytosis, and promotes cancer drug resistance by fueling ABC transporters and increase its efflux activities3. However, whether extracellular ATP can indeed enhance efflux of drugs, and the underlying mechanism besides providing energy remain unclear. Our current study results showed extracellular ATP decreased intracellular accumulation and thereby enhanced efflux of 3H-labeled chemotherapeutic drug and targeted drug in human cancer cells. The results of quantitative reverse transcription PCR, western blot and immunofluorescence microscopy demonstrated that extracellular ATP can also significantly upregulate ABC transporters at mRNA and protein levels, and change the intracellular localization of the latter. These results suggest that extracellular ATP has profound regulatory effects on ABC transporters and thus promotes drug resistance, linking the ATP-rich tumor microenvironment with cancer drug resistance. The completion of the study will expand our understanding of the roles of extracellular ATP in cancer, and reveal new therapeutic targets for reducing drug resistance and enhance anticancer efficacy of chemotherapeutics and targeted drugs. 1. Pavlova N, Thompson C. Cell Metab. (2016) 23:27-47 2. Falzoni S, et al., Interface Focus. (2013) 3: 20120101 3. Wang X, et al., Oncotarget. (2017) 8(50):87860-87877 Citation Format: Haiyun Zhang, Xuan Wang, Xiaozhuo Chen. A new mechanism of drug resistance in cancer: Extracellular ATP-induced resistance through ATP internalization and upregulation of ATP-binding cassette multidrug transporters [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1108.